Integrated gut microbiome and metabolomic analyses elucidate the therapeutic mechanisms of Suanzaoren decoction in insomnia and depression models

Insomnia and depression are psychiatric disorders linked to substantial health burdens. The gut microbiome and metabolomic pathways are increasingly recognized as key contributors to these conditions' pathophysiology. Suanzaoren Decoction (SZRD), a traditional Chinese herbal formulation, has demonstrated significant therapeutic benefits for both insomnia and depression. This study aims to elucidate the mechanistic effects of SZRD on insomnia and depression by integrating gut microbiome and metabolomic analyses and to assess the differential impacts of SZRD dosages. Using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS), we identified 66 chemical constituents within SZRD. Behavioral assays indicated that low-dose SZRD (LSZRD) significantly ameliorated insomnia symptoms in rat models, whereas high-dose SZRD (HSZRD) markedly improved depressive behaviors. 16S rRNA sequencing revealed that SZRD modulated gut microbiome dysbiosis induced by insomnia and depression, characterized by an increased abundance of short-chain fatty acid (SCFA)-producing genera. Metabolomic profiling demonstrated reduced plasma amino acid metabolites and disrupted <i>γ</i>-aminobutyric acid (GABA) and L-glutamic acid metabolism in the hippocampus of affected rats. SZRD administration restored fecal SCFA levels and ameliorated metabolic imbalances in both plasma and hippocampal tissues. These findings underscore the pivotal role of gut microbiome modulation and metabolic regulation in the therapeutic effects of SZRD, providing a scientific basis for its use in treating insomnia and depression.